Phenolphthalein compounds and methods of producing the same



Patented Oct. 8, 1940 PHENOLPHTHALEIN COMPOUNDS AND METHODS OF PRODUCING THE SAME Stanley E. Cairncross, Winchester, Masa, assign or to Bristol-Myers Company, New York, N. Y.,

a corporation of Delaware No Drawing. Application August 19, 1939,

Serial No. 290,943

'38 Claims.

This invention relates to glycosides of phenolphthalein, and to a method of making the same.

Phenolphthalein is used extensively as a laxative. However, such use is limited because it is quite insoluble in water, having a solubility of only 0.02 part in 100 parts of water at 20 C. Since the average dose of phenolphthalein is about 0.06 to 0.18 gram, it would therefore require about 300 c. c. to 900 c. c. of water to effect solution of a single dose. Accordingly, it would be impracticable to prepare and distribute an aqueous solution of phenolphthalein as a commercial product because it would be too bulky.

Soluble compounds of phenolphthalein, such as the sodium salt, have been made. compounds are exceedingly bitter, strongly colored and unstable in solution, and for these and other reasons their use for medicinal purposes is restricted or undesirable.

It is therefore an object of this invention to prepare compounds of phenolphthalein which are much more soluble in water than phenolphthalein and which are more easily administered and are presented to the fluids of the human system in a different form from the customary phenolphthalein, and in which, moreover, the phenolphthalein component is at the same time readily available to perform its laxative or other therapeutic functions.

Another object is to provide some compounds of phenolphthalein which are preferably essentially colorless, and either substantially tasteless or at least palatable.

A further object is to provide a class of compounds or derivatives of phenolphthalein which are new compositions of matter, per se, and which may be useful, if not as medicinal agents then for such other purposes as their specific characteristics may render them suitable.

Another object is to provide a method of making such derivatives or compounds.

Other objects will appear from the following disclosure. I

The class of compounds or derivatives'to-which this invention relates are the glycosides of phe-- nolphthalein. These derivatives are compounds which are generically constituted by the union of phenolphthalein and a sugar. The terms glycosides and glucosides have heretofore been used more or less as equivalents. But properly the former is the broader term and includes the latter group of compoundsand this is the more cur-rent usage at the present time.

Generically, a glycoside is a derivative of a sugar cyclic heml-acetal, formed by the etherifi- But such cation of the hemi-acetal hydroxyl group with a hydroxy-carbon compound, and has the property of furnishing a sugar and Oneor more other products when hydrolyzed by acid.

In the present description and in the following 5 claims, phenolphthalein "glycosides are to be considered as the class of products resulting from the union of phenolphthalein and a sugar by etherification, to form a derivative of a sugar cyclic hemi-acetal, having the property of fur-.

nishing a sugar and free phenolphthalein when hydrolyzed by acid.

In the molecular structure of the glycosides obtained by the method of the present invention, one oxygen atom of the sugar radical bridges 15 between the reducing carbon atom and a carbon atom of the chain of the sugar radical, while another oxygen bridges between the reducing carbon atom and one of the carbon atoms of phenolphthalein to effect, in all, a cyclic mixed acetal or glycoside structure. A typical illustration of a this structure is given in the following formula, in which the sugar is a typical aldohexose such as glucose, and P represents a phenolphthalein radical: 25

H H HOHC-C(CHOH)r-CO -P Using a similar sugar, a typical diglycoside of phenolphthalein may therefore be represented as follows:

' H 11 HOHzC'C(CHOH):-C

. component is a glucose residue or radical.

The sugars capable of use in the present method and of constituting a component of the glycosides produced thereby include trioses, tetroses, pentoses, methyl pentoses, hexoses, and also the lower; reducing poly-saccharid sugars having two, three or four mono-saccharide components,

Hence the gylcosides may which are characteristically soluble in water and may be referred to, as a group, as the reducing oligo-saccharides. They may be of aldose or ketose structure and may present various isomeric arrangements of molecular structure and still be applicable for use, as hereinafter more fully described, so-long as they are capable of existing in the form of a cyclic hemi-acetal and entering into and constituting the final product as above defined.

The lower reducing poly-saccharide or reducing oligosaccharide sugars are capable of forming glycosides and in fact are in themselves combinations of mono-saccharides in a form similar to the structure of the glycosides and may be hydrolyzed as by acids into component monosaccharides. For example, lactose is a galactosido-glucose, maltose a glucosido-glucose, and so on for other oligo-saccharides. Sugar-like poly-saccharides or oligo-saccharides resemble mono-saccharides in many of their chemical properties as well as in having, in general, a high solubility in water and a sweet or pleasant taste. Non-sugar-like poly-saccharides, or higher polysaccharides such as the starches and cellulose, on the other hand, while being condensation products of mono-saccharides, are relatively insoluble in water and differ from them in chemical properties also, Because of these differences they are not included in the present invention.

As is well known, the mono-saccharides are divided into two groups, the aldoses and the ketoses, according to whether they are respectively hydroxy-aldehydes or hydroxy-ketones. They are also classified in accordance with the number of carbon atoms or in accordance with the number of oxygen atoms present in the moleculee. g., as tetrose, pentoses, hexoses, etc. Furthermore, since all mono-saccharides except the two simplest ones have one or more asymetric carbon atoms, they must occur in stereoisomeric forms, thus making possible a large number of sugars differing only in atomic arrangements but similar in chemical structure and reaction.

It has also been found that reducing saccharides can exist in two forms-which are called the a and 5 forms. This follows from the fact that the mono-saccharides do not exist wholly in the open-chain form, but rather as, or in equilibrium with, the cyclic hemi-acetal form, viz:

cmoircnon.(onomtcnozcmoaoH. cnoma.0110B and this cyclic form presents a new asymmetrical carbon atom, represented by the asterisk For each open chain saccharide there may therefore be two isomeric cyclic formswhich differ only in the arrangement of the'groups around the carbon atom represented above by the asterisk. The a and 9 forms are distinct compounds, and differ in solubility, melting points of their derivatives, and optical properties. exist in either the a or the 5 form.

In the diglycosides of the present invention, the two saccharide radicals will ordinarily be identical. However, this invention is not so limited, and is intended to include diglycosides of phenolphthalein wherein the two saccharide radicals are different. These saccharide radicals may thus differ as between monoand oligosaccharides, or between aldoses and ketoses, or between pentoses and hexoses, or between (1 and l sidered as having four steps.

cipally of alpha glucose pentacetate.

forms, or between alpha and beta forms, or between two or more combinations of these, for

example.

A suitable procedure for preparing the new compositions of this invention may be summarized briefly as follows: The desired sugar is reacted with acetic anhydride to convert it into the corresponding polyacetate; this product is then reacted with hydrogen bromide to convert it into the corresponding acetobrom compound; this in turn is reacted with phenolphthalein to produce the polyacetyl-glycoside of the phenolphthalein, which is then treated to split off the acetyl radicals and give the final phenolphthalein glycoslde.

The same procedure is followed whichever sugar is used, hence the following detailed example, wherein the sugar is glucose, will be a sufficient illustration of the prcedure, which may be carried out with any other suitable sugar of the class above defined.

The procedure as outlined above may be con- Each of these steps will be described in detail, in the example to be described below. When the final product is to be used for medicinal purposes, special care should of course be taken to use pure materials and inert apparatus. When the product is to be used for other than therapeutical purposes, however, the materials, apparatus and procedure may be less rigorously controlled accordingly.

EXAMPLE I Preparation of phenolphthalein di-beta-glucoside Step 1.Preparation of glucose pentacetate. This step may be carried out in the following manner: Mix 700 grams anhydrous glucose and 250 to 350 grams anhydrous sodium acetate in a suitable flask, and add 3500 grams acetic anhydride. The fiask is held in a water bath at about 85 C., and the contents stirred intermittently to prevent localization of heat while the reaction proceeds, which requires about an hour. The

resulting mixture is then held at that temperature for about two hours, after which it is added slowly over a period of about one-half hour to about ten times its volume of ice water, with vigorous stirring. The product precipitates in the form of white crystals, which are removed from the liquid phase by filtration and dried carefully-first in the air for about 12 hours and then for 4 to 5 hours in a forced-draft oven at about 60 C. The yields from several runs ranged from to 90% of the theoretical, based on the original glucose: Average yield was 1300 grams, or of theoretical, of the product, which is glucose pentacetate.

- Step 2.Preparation of acetobromglucose.

Acetobromglucose (tetra acetyl glucosidyl bromide) may be prepared by the direct reaction in glacial acetic acidof HBr and glucose pentacetate, prepared as described above and consisting principally of beta glucose vpentacetate or prepared in some other manner, for example, with zinc chloride as a catalyst and consisting prin- This method has been adopted in carrying out Step 2 of the present procedure, which is performed as follows: Mix 1000 grams of the glucose pentacetate obtained as in Step 1 with 2000 grams of an 18 to 20% solution of HBr in glacial acetic acid, and agitate until solution is complete; let this solution stand at room temperature for about 2 hours. Then add a selective solvent for the aa epsc' w form solutioniof acetobrom'glu'c'ose and wash it,

first with ice-water, then with a suitable neutralizing agent for any traces of acetic acid and I-IBre. g., an ice-cold sodium bicarbonate solu tionand finally with ice-water again. The re-Y suiting neutral chloroform solution is dried to remove any water, present, as by mixing with anhydrous Na2SO4, and separating from the l Na2SO4 as soon as the chloroform solution is clear- The yields of the crystallized product from several runsranged from 60 to of the theoreti-' cal based on the glucose pentacetate.

If desired-theacetobromglucose may be separated from the chloroform solution in known manner by partially evaporating the chloroform solution at 50 C. under reduced pressure to form a thick syrup, washing with a little dry ether, and adding 15 to 20 volumes of petroleum ether to precipitate the acetobromglucose as a thick syrup which on cooling, with stirring, crystallizes and is then filtered off. It may be further purified by redissolving in dry ether and then evaporating the ether. Other procedures may be used for recovering the acetobromglucose.

Step 3(A) .-Preparation ofv phenolphthalein di-beta-tetracetyl glucoside. Acetobromglucose prepared in accordance with Step 2 is reacted with phenolphthalein in the presence of substances which are effective to remove the I-IBr and preferablywater which are produced by the reaction. It is important that this removal take place during the reaction, as the HBr tends to reverse the reaction and/or to cause undesirable side reactions, while the water tendsto decom pose the acetobromglucos'e. The acetobromglucose used in this step maybe either the dry crystalline solid, or the chloroform solution, the preparation of each of which is described in Step 2. Alternatively, the acetobromglucose may be prepared in other ways.

One method of carrying out Step 3 is as follows:

Ingredients: Acetobromglucose grams' 411 (1 mol) Phenolphthalein do 213 (0.6711101) Quinoline c. c.-- 250 Silver oxide grams 250 Dioxane c. c.-- 200 It is desirable to, have all the ingredients pure and waterand alcohol-free.

The phenolphthalein and quinoline are mixed; the dioxane'and acetobromglucose are added and the mixture stirred. The acetobromglucose may be in chloroform solution when added, or it may be dry, in which event chloroform should be added to effect solution. The silver. oxide is then added preferably in several successive steps, while stirring and keeping the mixture at a temperature of not over 45 C. After heat evolution ceases, stirring is continued for one to two hours, keeping the mixture at about 40 G. Then the solid resi-' dues (chiefly silver bromide and any excess silver oxide) are removed by filtration, and washed with chloroform until substantially colorless, the washings being combined with the filtrate. The filtrate, after treating with zinc dust, is then concentrated as nearly dry as possible, under reduced pressure, and preferably at a temperature not over 60 C., and the residue taken up in 750V 0. c. of hot ethyl alcohol and then refrigerated, whereupon crystals separate and arefiltered off, with thorough washing with cold 95%: ethyl alcohol.

The resulting filter cake of crude phenolphthalein di-beta-tetracetyl-glucoside is dissolved. in 1.5 times its weight of glacial acetic acid with warming and recrystallized by additionof 14 parts of 95% ethyl alcohol and cooling (e. g., to about-5' to 10 (3.). The resulting product is phenolphthalein di-bet'a tetracetyl-glucoside. The yields from several typical runs ranged between 30% and 50% of theoretical, based on the acetobromglucose.

Step 3(B)The foregoing procedure maybe modified to advantage'in several ways, some of which are indicated below.- Thus, starting with the same amount of acetobromglucose, the amount of'phenolphthale'in may be between grams (0.5 mol) and 640 grams (2 mols), the quinoline and dioxane may be omitted, and a suitable drying agent may be added such as Drierite, which is a trade name for a specially prepared form of anhydrous calcium sulfate in the form of porous pellets which are capable of taking up one-half mol of water (to form 2CaSO4.Hz0) while still retaining their shape. This is preferable to the use of the ordinary semihydrate (plaster-of-Paris), as the latter on.

addition of water sets to a solid cake which is difficult to manipulate or separate.

With these modifications, the procedure is as follows, starting with the same amount of acetobromglucose as above. The phenolphthalein, the silver oxide, and the Drierite? (about 400 to 500 grams) are mixed with part of the chloroform and stirred for anhour or so to complete drying. The acetobromglucose with the balance of the chloroform (total about 2000-3000 0.0. of chloroform from both sources) are added slowly enough to control heat evolution due to the reaction.

After the reaction is completed, as evidenced by absence of further evolution of heat and absence of bromide ion in the solution, the Ag Br and any excess AgzO and phenolphthalein are removed and subsequent steps followed as in the quinoline procedure just described. The purification is, however, somewhat simpler than when using quinoline, as the solutions obtained are much easier to concentrate to dryness. Furthermore, less effort is required to obtain a pure product; the solutions are light in color and fairly clear as compared with those using quinolin which are dark or even almost black.

The choice of solvents used depends on results and course of reaction desired. E.g., chloroform dissolves acetobromglucose but not phenolphthalein. Phenolphthalein is soluble in dioxane, however. Hence the solvents may be chosen so as to dissolve one or both principal reagents, as well as with respect to the product, which may or may not be precipitated accordingly.- a

The phenolphthaleindl-beta-tetracetylgluacetone, chloroform, nitrobenzene, and pyridine,

as well as in various other solvents. It is, however, insoluble or practically so in water and in carbon tetrachloride, and sparingly soluble in hot ethyl alcohol.

An analysis of a typical sample of the phenolphthalein di-beta-tetracetyl glucoside gave the following results:

Step 4.Preparation of phenolphthalein dibeta-glucoside. The product of Step 3 is deacetylated to give the final product. This may be done by following usual deacetylating procedure; thus, in the present instance, the phenolphthalein dibeta-tetracetyl-glucoside is refiuxed for l to 2 hours with about twice its weight of substantially anhydrous methyl alcohol containing sodium methylate in an amount such that its sodium content is equal to about 0.1% of the glucoside compound. The sodium methylate acts to catalyze the reaction, which is one of alcoholysis. The reaction is substantially complete when all the phenolphthalein di-beta-glucoside is in solution. Carbon dioxide is then passed into the solution to decompose the sodium methylate, thus combining with the sodium to form sodium carbonate. This sodium carbonate, which is insoluble in the reaction mixture, is largely removed by filtration-with the use of activated 7 carbon as a filter aid if desired. The filtrate is evaporated to dryness to remove the methyl acetate produced and the excess methyl alcohol, and the dry product is phenolphthalein di-beta-glu coside. The yields are practically theoretical. The methyl alcohol is used in excess because it serves as a solvent for the product as well as to react with the starting material. Other anhydrous low-boiling alcohols, such as ethyl, in which the final product is soluble, may be used in place of methyl alcohol, although methyl alcohol appears to work most satisfactorily. De-acetylation may also be effected with other reagents such as ammonia or barium hydroxide.

Phenolphthalein di-beta-glucoside is a new compound, and has the molecular formula (33211-134014, which may also be represented as C2oHi2O2(OCeH1iO5) 2, and hence has a calculated formula weight of 642. It is very soluble in water and in the lower alcohols such as methyl and ethyl alcohols, and also in pyridine. It is insoluble in chloroform, acetone, and petroleum ether, and only very slightly soluble in hot nitrobenzene. Its exact solubility in water is not readily determined, as it dissolves therein in an amount at least sufficient to form a syrupy solution. It is a white powdery solid. The optical rotation of several representative samples in water ranged between 48.9 and 50.4, averaging [dig-493 It does not reduce Fehling's solution.

Clinical and toxicity tests years to 86 years of age, in comparison with ordinary phenolphthalein. These tests showed that the phenolphthalein di-beta-glucoside was at least as effective, weight for weight, as phenolphthalein, and in a number of cases was at least twice as eflective. No unfavorable reactions to either compound were observed.

General ein; these can easily be treated to render themv suitable for reuse.

EXAMPLE II Preparation of phenolphthalein di-beta-galactoside Phenolphthalein di-beta-galactoside is prepared by the procedure as described in Example I, except that in Step 1 the glucose is replaced by an equal weight of galactose.

The final product is a white crystalline solid having the same molecular formula and molecular weight asthosealreadygivenforphenolphthalein di-beta-glucoside. It has a melting point of 162-164" C. It is very soluble in methyl alcohol, fairly soluble in hot or cold acetone or pyridine, hot nitrobenzene and hot ethyl alcohol, but less soluble in cold ethyl alcohol.v It is insoluble in chloroform or petroleum ether. It is only slightly soluble in water, to the extent of about 1% in hot water and less in cold water. It does not reduce Fehlings solution. Rotation of a representative sample was in absoluble methyl alcohol.

The intermediate product, phenolphthalein dibeta-tetracetyl-galactoside, is a white powdery solid having the same molecular formula and formula weight as those already given for phenolphthalein di-beta-tetracetyl-glucoside. Itisreadily soluble in chloroform, fairly soluble in methyl alcohol, and practically insoluble in water. It is soluble in pyridine, acetone, and in ethyl acetate. The optical rotation of a representative sample was Preliminary tests have indicated that the phenolphthalein di-beta-galactoside is an even more effective laxative agent than the corresponding glucoside, and that it is comparable with the glucoside and with phenolphthalein in its non-toxic properties.

ADDITIONAL MODIFICATIONS 0F PROCEDURE Various modifications have already been given in the several steps for obtaining the products of the present invention. Other modifications are possible, of which the following will be mentioned:

Instead of the bromine compounds, the corresponding chlorine compounds may be made and used. Thus, acetochlorglucose may be the prodnot of Step 2 in Example I. As a rule, however, the bromine compounds are more active.

Also, the acetobrom (or chlor) glucose may be made by the acetyl halide synthesis, wherein acetyl bromide or acetyl chloride is reacted dipolyacyl-glycosides.

\ reduced to about rectly upon the glucose or other sugar in the I range between about 4.5 and 8.5.

presence of HBr or HCl or a, small amount of water. From the standpoint of yield, costs, and

operation, the procedure previously described herein is, however, generally preferable.

Again, the acetate radicals may be replaced] ein di-polyformyl (or poly-propionyl, or other polyacyl) glycosides; From the standpoint of ease of operation, and cost, these esters with the lower fatty acids, especially acetic, are preferred for use in the present invention. However, the esters may be made with other organic acids, e. g., with higher fatty acids, or with aromatic acids, thus providing .acylhalosaccharides as starting materials for Step 3 and giving as products of Step 3 phenolphthalein di-polyacyl-glycosides, for example phenolphthalein dipolystearyl-glyccsides, phenolphthalein di-poly-benzoyl-glycosides, etc.

Other hexose sugars than glucose and galactose may be used in the same manner, such sugars including both ketoand aldo-hexoses. Similarly, PBIlLOSES and lower mono-saccharides may be employed, as well as the reducing oligo-saccharides hereinbefore referred to.

Hence the products of the present invention are more especially the phenolphthalein glycosides and the corresponding phenolphthalein Ordinarily, in any given diglycoside of either type, both saccharide radicals will be identical, and many given compound of the second (the polyacyl) type, all the acyl radicals will beidentical. It would be possible, however, although hardly practical under any ordinary circumstances, to have different saccharide radicals, or to have different acyl radicals, or both.

FORMULATION While the di-glycosides of phenolphthalein are not all equally soluble in water, they are as a rule sufficiently soluble to permit of being compounded into aqueous concentrates or elixirs of sufficient strength that one or two teaspoonfuls oi the concentrate or elixir contain enoughof the phenolphthalein di-glycoside to be. adequate for an average normal dose as a laxative. This contrasts with about 300 c. c. of water necessary to take up an equally effective amount of phenolphthalein, as already pointed out.

Formulation of an elixir of a phenolphthalein di-,'lycoside may be carried out as follows: Boil together 450 grams of water, 380 grams of cane sugar, and 11 grams of phenolphthalein di-glucoside, stirring to promote solution. Then cool, ani. filter if desirable. Mix the resulting solution With a second solution made of 100 c. c. of ethyl alcohol, 25 c. c. of water, and sufficient flavoring, e. g., 10 c. c., and make the resulting solution up to one liter with water. Elixirs so prepared have shown no tendency to ferment," decompose, or otherwise change or lose their efficacy, unless appreciably on either the acid or alkal no side of neutrality. Such acidity or alkalinity would only beintroducecl by the flavoring or other ingredients of the elixir, and hence can be readily avoided in the formulation. The preferred pH range is between about 4.5 and 9.5.

However, if the elixir is likely to be exposed to While a detailed description 1' the production of particularphenolphthalein di-polyactyl-glycosides and phenolphthalein. di-glycosides', and of v the use of the latter group of compounds-as laxative agents, has been givenyit should, of course,

' a l 1. 8.5-i. a; ,with an loverall prrf be understood that these compounds, being new; J

compositions of matter, are not herein restricted to any single specific use but may be utilized for various purposes; and furthermore, that the description herein is given by way of illustration, and that the scope of the invention is therefore to be considered'as limited only by the scope of the appended claims. I v

I claim: 5

1. Method of preparing compounds of phenolphthalein, which comprises reacting phenolphthalein with an acyl-halo-saccharide, in the presence of a reagent to remove the'halogen, to form a phenolphthalein acyl glycoside.

2. A method according to claim 1 in which the acyl halo-saccharide is a saccharideof the class consisting of bromo and chloro saccharide esters of the lower fatty acids;

3. A method according to claim 1 in which the acyl-halo-saccharide is an} acetyl bromo saccharide. l

4. Method of preparing compounds ofphenolphthalein, which comprises reacting phenolphthalein with an acyl-halo-saccharide, in the presence of a solvent for at least one of the reacting ingredients and a reagent to remove the halogen in the form of halide which is inert toward the product, to form aphenolphthalein acyl glycoside.

5. Method of preparing compounds of phenol- -phthalein. which comprises reacting phenolphthalein with an acyl-halo-sac'charide, in the presen.:e of a solvent anda reagent to remove the halogen in the form of an insoluble halide, to form a phenolphthaleinacyl glycoside. g

'7. Method of preparing compoundsoi phenol phthalein, which comprises reacting phenolphthalein with an acyl-haloemono-saccharide, in

the presence of a solvent and a reagent to'remove the halogen in the form of an inert halide, to

form a phenolphthalein acyl glycoside.

8. Method of preparing compounds of pl le'n 'ilphthalein, which comprises reacting phen'olphthalein with an acyl-halo-poly-saccharide,in;

the presence of a solvent and a reagentjto re- 60 move the halogen in the form ,ofan inert halide, to form a phenolphthalein acyl glycoside'."

9. Method of preparing compounds'of phenol phthalein, which comprises reacting: phenol-.

phthalein with an acyl-halo-saccharide;in the.

presence of a reagent to remove the'halogen, to form a phenolphthalein acyl di-glycoside. Y 1

10. Method of preparing compounds of phenol-,-

phthalein, which comprises reactingphenolj phthalein with an acyl-halo-mono-saccharide,in the presence of a solvent'ior one of; the reacting ingredients and a reagent to remove the halogen as a halide which is inert to the product,'to form v a phenolphthalein acyl di-beta-glycoside.

11. Method of preparing compouhdsjof phenol- I phthalein, which comprises reacting]phenol:

- the acyl-halo-saccharide is a saccharide of the class consisting of bromo and chloro saccharide esters of the lower fatty acids.

13. A method according to claim 11 in which the acyl-halo-saccharide is an acetyl bromo saccharide.

14. A method according to claim 1 in which the acyl-halo-saccharide is a monohalo saccharide.

15. A method according to claim 1 in which the reagent to remove the halogen is silver oxide.

16. Method of preparing compounds of phenolphthalein, which comprises reacting phenolphthalein with an acyl-halo-saccharide, in the presence of a solvent for at least one of the reacting ingredients, and a reagent to remove the halogen in the form of a halide which is inert toward the product, to form a phenolphthalein acyl glycoside, and deacylating the resulting phenolphthalein acyl glycoside to form a phenolphthalein glycoside.

17. Method of preparing compounds of phenolphthalein, which comprises reacting phenolphthalein with an acyl-halo-saccharide, in the presence of a solvent, a dehydrating agent, and a reagent to remove the halogen in the form of an inert halide, to form a phenolphthalein acyl glycoside, and de-acylating the resulting phenolphthalein acyl glycoside to form a phenolphthalein glycoside.

18. Method of preparing compounds of phenolphthalein, which comprises reacting phenolphthalein with an acyl-halo-saccharide, in the presence of a solvent and a reagent to remove 'the halogen in the form of an insoluble halide, to

form a phenolphthalein acyl glycoside, and deacylating the resulting phenolphthalein acyl glycoside to form a phenolphthalein glycoside.

19. Method of preparing compounds of phenolphthalein, which comprises reacting phenolphthalein with an acyl-halo-mono-saccharide, in the presence of a solvent and a reagent to remove the halogen in the form of an inert halide, to form a phenolphthalein acyl glycoside. and deacylating the resulting phenolphthalein acyl glycoside to form a phenolphthalein glycoside.

20. Method of preparing compounds of phenolphthalein, which comprises reacting phenolphthalein with an acyl-halo-poly-saccharide, in the presence of a solvent and a reagent to remove the halogen in the form of an inert halide, to form a phenolphthalein acyl glycoside. and deacylating the resulting phenolphthalein acyl glycoside to form a phenolphthalein glycoside.

21. Methodof preparing compounds of phenolphthalein, which comprises reacting phenolphthalein with an acyl-halo-saccharide, in the presence of a solvent for at least one or the reacting ingredients and a reagent to remove the halogen in the form of a halide which is inert toward the product, to form a phenolphthalein acyl-di-glycoside, and de-acylating the resulting phenolphthalein acyl di-glycoside to form a phenolphthalein (ii-glycoside.

22. As a new class of chemical compounds, the glycosides of phenolphthalein.

23. As a new class of chemical compounds the di-glycosides of phenolphthalein.

24. As a new class of chemical compounds, the acyl-glycosides of phenolphthalein.

25. As a new class of chemical compounds, the acyl-di-glycosides of phenolphthalein.

26. As a new class of chemical compounds the glucosides of phenolphthalein. L

27. As a new class of chemical compounds the acyl glucosides of phenolphthalein.

28. As a new chemical compound the di-tetraacetyl glucosicle of phenolphthalein.

29. As a new chemical compound, di-beta glucoside of phenolphthalein.

30. As a new chemical compound, di-beta ga' lactoside of phenolphthalein. I 31. A laxative including a glycoside of phenolphthalein.

32. A laxative including a di-glucoside of phenolphthalein.

33. A laxative including a di-galactoside of phenolphthalein.

34. A laxative elixir comprising a solution of a glycoside of phenolphthalein.

35. A laxative elixir comprising a solution of a di-glycoside oi phenolphthalein.

36. A laxative elixir comprising a solution of a glucoside of phenolphthalein.

37. A laxative elixir comprising an aqueous solution of di-beta glucoside of phenolphthalein.

38. A laxative elixir comprising a solution of a galactoside of phenolphthalein.

STANLEY E. CAIRNCRQSS. 

